This project tests specific hypotheses about structural and functional brain abnormalities in elderly patients with late-onset major depression. Prior research indicates that elderly depressed patients have marked deficits in the global and topographic distributions of cerebral blood flow (CBF) and metabolism (CMR). Both patient age and symptom severity may be related to the extent of topographic disturbance. There is now evidence that neither the global or topographic CBF deficits resolve when patients become euthymic. Indeed, response to ECT has been linked to further CBF reduction, while the effects of treatment with antidepressant medications on CBF or CMR are largely unknown. Elderly depressed patients also have excessive rates of encephalomalacia-MRI hyperintensities in subcortical gray matter structures and deep white matter. Based on associations with risk factors, and histology and in vivo perfusion imaging in other populations, the predominant view is that encephalomalacia is frequently an outcome of cerebrovascular disease (CVD) resulting in ischemic changes in poorly irrigated tissue. However, the relations between the rCBF,rCMR, and MRI abnormalities in major depression are unknown, and no study has quantified CBF in the areas of the MRI hyperintensities or assessed hemodynamic reserve in major depression. In this project, 80 patients with late-onset, nonpsychotic, major depression and 40 matched controls will be studied. Subjects will undergo psychiatric, neurological, and neuropsychological evaluations, with special attention to CVD risk factors. Imaging will be conducted at baseline, after a 6-week medication trial, and two years later. We will test specific hypotheses about the functional abnormalities associated with the state of major depression and altered by effective antidepressant treatment, and the trait structural and functional abnormalities that may predispose to late-onset affective illness. These hypotheses are related to a more general theory that a disproportionately large number of the elderly depressed have a form of progressive CVD, with impairment in hemodymanic reserve. Establishing whether this is the case may not only have important implications for our understanding of the pathogenesis, but also of the phenomenology, treatment, and prevention of major depression in the elderly.